Copper-catalyzed hydrative amide synthesis with terminal alkyne, sulfonyl azide, and water

Article abstract of DOI:10.1021/ja056399e

It is shown for the first time that N-sulfonyl amides can be efficiently prepared by an unconventional approach of the hydrative reaction between terminal alkynes, sulfonyl azides, and water in the presence of copper catalyst and amine base under very mil

Full text of DOI:10.1021/ja056399e

Published on Web 11/01/2005
Copper-Catalyzed Hydrative Amide Synthesis with Terminal Alkyne, Sulfonyl
Azide, and Water
Seung Hwan Cho, Eun Jeong Yoo, Imhyuck Bae, and Sukbok Chang*
Center for Molecular Design and Synthesis (CMDS), Department of Chemistry and School of Molecular Science
(BK21), Korea AdVanced Institute of Science and Technology, Daejon 305-701, Republic of Korea
Received September 24, 2005; E-mail: sbchang@kaist.ac.kr
The amide group is a key motif in chemistry and biology.1
Although traditional chemical methods for simple amide synthesis
rely heavily on an interconversion strategy between carbonyl groups
Table 1. Hydrative Amide Synthesis under Various Conditionsa
2
or their equivalent reactive compounds, lability of those functional
groups often restricts its ubiquitous applications. Hence, the
development of alternative routes has been challenging to synthetic
chemists. As a result, the use of thio acids or thioesters as a
entry
catalyst
base
solvent
yield (%)b
3
1
2
3
4
5
6
7
8
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuBr‚SMe2
CHCl3
CHCl3
<1
95
27
47
35
<1
30
67
carbonyl precursor has been actively investigated as a chemical
Et3N
3
4
Et N (0.2 equiv)
(i-Pr)2NEt
pyridine
K2CO3
3
CHCl3
ligation method. The modified Staudinger reaction of azides with
CHCl3
phosphines has also drawn special attention to the chemoselective
CHCl3
CHCl3
THF
5
formation of amides. Separately, advances in the functionalization
of multiple bonds enabled facile conversion of unsaturated hydro-
Et N
Et N
3
6
CHCl3
carbons to the corresponding carbonyl compounds. Especially, the
hydration of alkynes is regarded as one of the most promising
reactions for this purpose, although the reactions proceed generally
at high temperatures. In this context, catalytic carbonylation of
a
Phenylacetylene (0.5 mmol), p-toluenesulfonyl azide (1.2 equiv), base
(
1.2 equiv except entry 3), water (2.5 equiv), and catalyst (0.1 equiv) in
7
solvent (1.0 mL). b Based on the integration of 1H NMR signals using
p-anisole as an internal standard.
alkynes with amines and CO of high pressure at high temperatures
8
offers a route to the synthesis of homologated amides.
the corresponding N-sulfonyl amides in high yields (Table 2).
Reactions with both aromatic and aliphatic 1-alkynes were efficient
and not influenced by the electronic and steric variations of the
reacting substrates. A variety of labile functional groups, such as
heterocyclic (entry 6), halide (entry 7), acetate (entry 8), silyloxy
Recently, we devised a highly efficient copper-catalyzed multi-
component reaction (MCR), in which sulfonyl azides react with a
9
wide range of alkynes and amines to give amidines. Whereas
electron-rich azides react with 1-alkynes mainly leading to 1,4-
triazoles using copper catalyst,10 the reactivity of sulfonyl azides
(
entry 9), propargylic ether (entry 10), conjugated olefin (entry 11),
varies significantly to result in a range of interesting amino group-
containing compounds depending on the third coupling partners.
In the course of our investigation on the mechanistic details of this
MCR, we found that a trace amount of amide was generated (e5%)
when aqueous cosolvent was used. This led us to delve into an
optimized preparation of amides. Herein we present an interesting
procedure for the amide synthesis based on the MCR employing
water as one reacting species under very mild conditions (eq 1).
and ester moiety (entry 12), were fully tolerated under the
conditions. Intriguingly, in the case of propargylic ether (entry 10),
the use of 2,6-lutidine resulted in much higher product yield than
Et N (34%). It should be mentioned that the reaction is regiose-
3
lective: only terminal alkynes react, while olefin and internal triple
bonds (entries 12 and 13, respectively) are intact.
In addition to aryl sulfonyl azides, aliphatic variants work equally
well. For instance, sulfonyl azides of phenylmethane, butane, and
2
-trimethylsilylethane took part in the reaction to afford the
1
3
corresponding N-sulfonyl amides in high yields (entries 14-16).
Moreover, N-camphorsulfonyl amide 3q was obtained in good yield
under the same conditions (entry 17).
The present approach to amide synthesis was readily amenable
to the solid-phase procedure (eq 2). A terminal alkyne (1r)
At the outset of our studies, we tried to optimize the reaction
conditions for the selective formation of amides (Table 1).11 When
the reaction of phenylacetylene (1a) with p-toluenesulfonyl azide
14
attached onto a 2-chlorotrityl resin was readily converted to the
corresponding supported N-sulfonyl amide under the similar condi-
tions, although the reagents were used in large excess compared to
(
2a) and water was tried with CuI in the absence of an external
12
base, no conversion was observed. In contrast, successful forma-
tion of N-sulfonyl amide 3a was observed in chloroform when a
15
solution-phase cases.
tertiary amine base, such as Et
amount of triethylamine is required to achieve high efficiency
compare entries 2 and 3), the use of other bases results in
3
N, was added. While a stoichiometric
3 2
After cleaving the resin using CF CO H, a derivative of hydroxy
sulfonamide (3r) was isolated in 46% overall yield from three steps,
indicating that each step proceeds in 77% on average.
(
16
significantly reduced yields (entries 4-6). Solvents other than
chloroform afforded low yield (entry 7), and copper catalysts other
than CuI exhibited reduced activities.
The present approach for amide synthesis turned out to be quite
general, and a wide range of alkynes and sulfonyl azides underwent
the coupling with water by the action of copper catalyst to furnish
16046
9
J. AM. CHEM. SOC. 2005, 127, 16046-16047
10.1021/ja056399e CCC: $30.25 © 2005 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Copper-Catalyzed Hydrative Amide Synthesisa
Although it is still early to present sufficient mechanistic
evidence, the reaction is thought to be initiated by the copper
catalyst to form an imidate intermediate followed by tautomerization
to afford the amide.18 It is also suspected that an amination of copper
acetylide to an N-sulfonyl ynamide takes place prior to the addition
19
of water to the allenamide tautomer leading to the amide product.
Release of N from sulfonyl azides during the course of either
2
process is also assumed: this drives the overall transformation.
Details on the mechanistic pathways will be presented in due course.
We demonstrate for the first time that amides can be prepared
practically by an unconventional hydrative reaction between
terminal alkynes, sulfonyl azides, and water in the presence of a
copper catalyst and amine under very mild conditions. Since alkynyl
and sulfonyl azido moieties are readily introduced and managed in
chemical processes, the developed route to amides is highly versatile
and has great potential as a synthetic tool.
Acknowledgment. This research was supported by grant No.
R01-2005-000-10381-0 from the Basic Research Program and
CMDS. We also thank Prof. David G. Churchill for his critical
reading of this manuscript.
Supporting Information Available: Experimental procedures,
1
13
spectroscopic data, and copies of H and C NMR spectra for the
prepared amide compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
References
(
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a
Alkyne (0.5 mmol), sulfonyl azide (1.2 equiv), Et3N (1.2 equiv except
in entry 10), and CuI (0.1 equiv) in CHCl3 (1.0 mL). b Isolated yield. c 2,6-
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The reaction can be also effectively scaled up with the similar
efficiency. For example, the reaction of propargylic amine derivative
(
(1s, 10.0 mmol) gave the corresponding â-amino sulfonamide (3s)
in high yield even when lower amounts of copper catalyst were
used (eq 3). Due to the fact that propargylic groups can be easily
introduced in the chemical synthesis via N- or O-alkylation, our
present protocol would be highly attractive as a viable and rapid
route to the generation of amides bearing heteroatoms at the
â-position.
(9) Bae, I.; Han, H.; Chang, S. J. Am. Chem. Soc. 2005, 127, 2038.
(10) Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K. B. Angew.
Chem., Int. Ed. 2002, 41, 2596.
(
11) For full optimization experiments, see Supporting Information (Table S1).
(12) On the basis of the kinetic observation of initial reaction rates, the reactivity
of water is 2 orders of magnitude lower than that of amine. See Supporting
Information for the comparison.
(13) Under the same conditions, treatment of methanesulfonyl azide with
phenylacetylene gave a meager 19% yield of the desired amide.
(
(
(
14) Walsh, D.; Wu, D.; Chang, Y.-T. Curr. Opin. Chem. Biol. 2003, 7, 353.
15) For experimental details, see Supporting Information.
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18) While it was observed that copper acetylide forms during the early stages
of the reaction, subject of separately prepared phenylethynylcopper(I) to
the reaction mixture of sulfonyl azide and water did not produce any amide
products. For the preparation of copper acetylide, see: Ito, H.; Arimoto,
K.; Sensui, H.; Hosomi, A. Tetrahedron Lett. 1997, 38, 3977.
(
(
Despite the fact that N-sulfonyl amides (N-acylsulfonamides)
themselves have a significant value in medicinal chemistry,17 we
found that removal of the N-sulfonyl group was readily carried out
in high yield with sodium in naphthalene,15 thus further applications
(19) For a recent review on ynamides, see: Zificsak, C. A.; Mulder, J. A.;
Hsung, R. P.; Rameshkumar, C.; Wei, L.-L. Tetrahedron 2001, 57, 7575.
of this protocol are feasible.
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